INTRODUCTION
Could the elixir of youth be as simple as a protein found in young blood?
Researchers studying mice found that giving old animals blood from young ones can reverse some signs of aging, and in 2013 one team identified GDF11 as a growth factor in the blood that they think is partly responsible for the antiaging effect on a specific tissue, the heart. Now, that group has shown this same factor can also rejuvenate muscle and the brain. 'Rejuvenation Factor' in Blood Turns Back the Clock in Old Mice.2014
DEFINITION
GDF11 (45 kDa) also known as bone morphogenetic protein (BMP-11), encoded by GDF11 gene, is a member bone morphogenetic protein (BMP) family and the TGF-beta superfamily. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. GDF11 is an homodimer disulfide-linked protein, composed by 407 aminoacids.
THE GENE
In human the GDF11 gene is localized on the 12 (location Chromosome 12: 56,137,064-56,150,911).
Official Symbol: GDF11
Other Designations: BMP11
The GDF11 gene is expressed in the pancreas, intestine, kidney, skeletal muscle, and developing nervous system.
Deletion of the GDF11 gene in mice causes anterior homeotic transformation of the axial skeleton with lumbar vertebrae transformed into thoracic vertebrae. GDF11-/- mice have malformations of the stomach, changes in the proportion of pancreatic cell types and die perinatally presumably due to developmental defects in kidney and palate formation Metabolic Functions of Myostatin and GDF11.2010
AMINOACIDS PERCENTAGE
DIAGNOSTIC USE
The role of GDF11 in cardiac hypertrophy
Cardiac Hypertrophy
Among the diseases and disorders associated with advancing age, one of the most debilitating is the loss of normal cardiac function leading to heart failure. Heart failure affects approximately 1% of individuals over 50 and over 5% of individuals over 75.
Most age-related heart failure occurs in the setting of normal systolic function and is called ‘‘diastolic heart failure’’, in contrast to ‘‘systolic heart failure’’. Although progress has been made in the treatment of systolic heart failure, with substantial improvements in outcome over the past two decades, progress in treating diastolic heart failure has been much more elusive. Indeed, one can argue that there are no specific therapies for patients who experience the ventricular ‘‘stiffening’’ associated with the diastolic dysfunction that accompanies aging. Emerging evidence indicates that systemic factors profoundly influence tissue aging. Some of these data have emerged from experimental model of parabiosis, which was first developed in the 19th century. Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy.2013
A powerful technique: PARABIOSIS
In parabiosis, two mice are surgically joined such that they develop a shared blood circulation with rapid and continuous exchange of cells and soluble factors at physiological levels through their common circulatory system. The pair of animals may be the same age ( isochronic parabionts ) or different ages ( heterochronic parabionts ). Because parabiotic mice are connected solely through their common circulation, parabiosis is a powerful model to determine whether circulating factors can alter tissue function.
Heterochronic parabiosis experiments suggest that blood-borne signals from a young circulation can significantly impact the function of aging tissues, as indicated by the restoration of appropriate activation and function of endogenous, ‘‘old’’ skeletal muscle satellite cells and successful muscle repair after injury following exposure to a ‘‘youthful’’ systemic milieu. Conversely, exposing a young mouse to an old systemic environment can inhibit myogenesis and neurogenesis in the young mouse. Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy.2013
Heterochronic Parabiosis Reverses Age-related Cardiac Hypertrophy
Left ventricular hypertrophy is an important feature of cardiac aging, contributing to diastolic dysfunction and heart failure with preserved systolic function. Moreover, patients with diastolic dysfunction tend to be older and are more likely to be obese, diabetic, hypertensive, and female, compared to patients with systolic dysfunction suggesting distinct underlying pathological mechanisms.
The aging of cardiac phenotype is reversible upon exposure to factors in a young circulation, this younger look was obtained using surgically anastomosed parabiotic mice. The exposure of old mice to a young circulation via parabiosis reproducibly led to a reversal of cardiac myocyte hypertrophy in a gender-independent fashion and this reduced cardiomyocyte size translated into a reduction in global cardiac mass. This structural transformation is accompanied by a reduction in myocardial gene expression of natriuretic peptides known to promote maladaptive cardiac remodeling and an increase in Ca2+ ATPase (SERCA-2), the expression of which is integral to myocardial relaxation and hence normal diastolic function.
GDF11 emerged as a strong candidate factor present at higher levels in the blood of young mice and can mediate the antihypertrophic effect. Although GDF11 expression is detectable in a range of tissues, the spleen shows the highest concentration and exhibits an age-dependent decline in GDF11 levels. Thus, the spleen may contribute to circulating GDF11, and an age-related production or secretory defect in the spleen could participate in the reduction in circulating GDF11 in old mice.
The treatment of cachexic mice with soluble ActRIIB protein (sActRIIB), which antagonizes signaling by GDF11 (as well as myostatin, activin, and other TGF-b family members, given the promiscuity of the receptors) reverses cardiac atrophy in tumor-bearing animals. Furthermore recombinant GDF11 (rGDF11) therapy for 30 days led to a significant regression of cardiac hypertrophy in old mice.
GDF11 is ineffective in preventing cardiac hypertrophy in the context of pressure overload, for these reasons the antihypertrophic properties of GDF11 may not be generalizable to all forms of cardiac hypertrophy.
GDF11 is implicated in age-related cardiac hypertrophy but it is not excluded the participation of other factors. Currently, there are no evidence indicating a role for GDF11 in the development of age-related cardiac hypertrophy in humans, although GDF11 does stimulate phosphorylation of target protein (SMAD2/SMAD3) in human pluripotent cell-derived cardiomyocytes. Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy.2013
Recently identified in the circulation of humans, GDF11, like other TGF-b family members, circulates at significantly lower concentrations in humans compared to mice. Although low levels of GDF11 identify a cohort among humans with stable coronary artery disease with a higher risk for composite endpoint of all-cause mortality, myocardial infarction, heart failure, and stroke. Future studies will be necessary to evaluate the role of GDF11 in human cardiac hypertrophy, because cardiac hypertrophy of aging is a multifactorial process and the observed regression of cardiac hypertrophy in old mice exposed to a young circulation is unlikely to be attributable entirely to the replenishment of a single factor but there are therapeutic possibilities for targeting cardiac hypertrophy of aging by restoring youthful levels of circulating GDF11.
Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy.2013
GDF11 effects on other tissues
4 weeks of daily GDF11 injections works nearly as well as parabiosis in helping elderly mice recover from a muscle injury and boosts their performance on running and grip strength tests.
GDF11 also encourages growth of new blood vessels and olfactory neurons in the mouse brain.
In both muscle and the brain, GDF11 appears to work in part by restoring the function of aging stem cells so that they can differentiate into adult tissues.
Parabiosis can rejuvenate another part of the mouse brain, the hippocampus, where memories are made and stored. Old mice that underwent parabiosis formed more new connections between nerve cells there.
Although no rejuvenation factors from the young blood have been isolated, giving old mice injections of young mouse plasma, or blood from which red and white cells have been removed, can bring to similar effects on the hippocampal neurons. The old mice also performed significantly better than untreated animals on tests of learning and memory.
A company is planning a small clinical trial that would give Alzheimer's patients a series of injections of plasma from young donors. In mouse models of Alzheimer's, researchers have already seen positive effects. 'Rejuvenation Factor' in Blood Turns Back the Clock in Old Mice.2014
Conclusion: “Vampire Therapy” could reverse ageing
A trasfusion of youthful blood may halt or even reverse the ageing process as these studies find that the chemical make-up of younger blood has surprising health benefits. It may seem the stuff of gothic horror novels, but transfusions of young blood could reverse the ageing process and even cure Alzheimer’s Disease. 'Vampire therapy' could reverse ageing, scientists find.2014
This is the first demonstration of a rejuvenation factor that is naturally produced, declines with age, and reverses aging in multiple tissues. 'Rejuvenation Factor' in Blood Turns Back the Clock in Old Mice.2014
| Author: Laura Follia e Federica Vercelli |
